It is now well established that angiogenesis is an important contributor to the pathogenesis of a variety of disorders. These include solid tumors and metastasis, atherosclerosis, retrolental fibroplasia, hemangiomas, chronic inflammation, intraocular neovascular diseases such as proliferative retinopathies, e.g., diabetic retinopathy, retinal vein occlusion (RVO), age-related macular degeneration (AMD), neovascular glaucoma, immune rejection of transplanted corneal tissue and other tissues, rheumatoid arthritis, and psoriasis. Duda et al. J. Clin. Oncology 25(26): 4033-42 (2007); Kesisis et al. Curr. Pharm. Des. 13: 2795-809 (2007); Zhang & Ma Prog. Ret. & Eye Res. 26: 1-37 (2007).
In the case of tumor growth, angiogenesis allows tumor cells to acquire a growth advantage and proliferative autonomy compared to normal cells. A tumor usually begins as a single aberrant cell which is able to grow only to a size of a few cubic millimeters due to the distance from available capillary beds and it can stay ‘dormant’ without further growth or dissemination for a long period of time. Some tumor cells then switch to the angiogenic phenotype to activate endothelial cells (ECs), which proliferate and mature into new capillary blood vessels. These newly formed blood vessels not only allow for continued growth of the primary tumor, but also for the dissemination and recolonization of metastatic tumor cells. The mechanisms that control the angiogenic switch are not well understood, but it is believed that neovascularization of tumor mass results from the net balance of a multitude of angiogenesis stimulators and inhibitors.
To date, a significant number of molecules, mostly secreted factors produced by surrounding cells, have been shown to regulate EC differentiation, proliferation, migration and coalescence into cord-like structures. For example, vascular endothelial growth factor (VEGF) has been identified as the key factor involved in stimulating angiogenesis and in inducing vascular permeability. Ferrara et al., Endocr. Rev. 18:4-25 (1997). In addition, an ECM-associated protein designated epidermal growth factor-like 7 (EGFL7) has been shown to be expressed by endothelial cells and to have a role in angiogenesis. Parker et al., Nature 428: 754-58 (2004); Fitch et al., Dev. Dynamics 230: 316-24 (2004); Campagnolo et al., Am. J Path. 167(1): 275-284 (2005); Schmidt et al., Development, 134(16): 2913-23. (2007), US patent application US2007/0031437. Fitch et al. also describe a paralog of Egfl7 designated Egfl8 and indicate that its expression is similar to that of Egfl7, but that EGFL7 and EGFL8 may not overlap in function.
Despite the many advances in the field of angiogenesis, there remains a need to identify targets and develop means that can supplement or enhance the efficacy of existing anti-angiogenesis therapies.